1. Field of the Invention
The present invention relates to novel clavulone derivatives, a process for preparing the same, and use of said clavulone derivatives as a medicine. More particularly, it relates to clavulone derivatives of the formula: ##STR2## wherein R.sup.1 and R.sup.2 combine together to form a keto group or either one of R.sup.1 and R.sup.2 is hydrogen atom and another one of them is hydroxy or acetoxy group, R.sup.3 and R.sup.4 are the same or different and are each hydrogen atom or acetoxy group, n is 0 or 1, provided that when the C--C bond between 8 and 12 positions is double bond, n is 0, a, b, c, d and e are each an integer of 1 or 2, and the dotted line means that the C--C bond is a single bond or double bond, or a salt thereof, and a process for preparing the clavulone derivatives, and use thereof as a medicine, particularly as an anti-inflammatory or an anti-tumor agent.
2. Description of the Invention
Some of the clavulone derivatives [I] are extracted from the soft coral Clavularia viridis and others are chemically derived from the extracted compounds. These clavulone derivatives [I] of the present invention have some pharmacological activities such as anti-inflammatory and anti-tumor activities and are useful as a medicine.
The clavulone derivatives [I] include one or more stereoisomers such as optical and/or geometrical isomers due to asymmetric carbon atom(s) and double bond(s) in those molecules, and these isomers are also included within the scope of the present invention.
The clavulone derivatives [I] include specifically the compounds of the following formulae and their salts. ##STR3## in the above formulae, Ac means acetyl group.
The compounds of the above formulae (1) to (13) are designated "clavulone-1" to "clavulone-13", respectively. The salts of the clavulone derivatives (I) include conventional pharmaceutically acceptable salts such as salts of alkali metals (e.g. sodium, potassium), salts of alkaline earth metals (e.g. magnesium, calcium), salts of amino acids (e.g. glutamic acid), or the like.
Among clavulone-1 to clavulone-13, clavulone-1 to clavulone-6 are isolated from the soft coral Clavularia viridis by the steps of extracting roughly the soft coral with methanol, concentrating the crude extract, extracting the concentrated solution with ethyl acetate after dissolving it in water, subjecting the extract to silica gel chromatography, eluting with a mixed solvent of benzene-ethyl acetate (10:1 by volume), separating three fractions containing clavulone-1 to clavulone-3 under detecting with thin layer chromatography (TLC, Kiesel gel 60, solvent, benzene-ethyl acetate=4:1 by volume), and further separating other fractions by changing the solvent to benzene-ethyl acetate=5:1 by volume under detecting with thin layer chromatography, from which clavulone-4 to clavulone-6 being isolated.
Clavulone-7 to clavulone-13 are chemically derived from the above clavulone derivatives isolated from the soft coral. That is, when clavulone-1, clavulone-2 and clavulone-3 are reduced with a borohydride catalyst such as sodium borohydride or lithium borohydride in a usual manner to give the corresponding compounds wherein the double bond in the cyclopentane nucleus is saturated and the keto group at 9-position is reduced into hydroxy groups, i.e. clavulone-7, clavulone-9 and clavulone-10, respectively. Treatment of the compounds obtained by the above reduction with a conventional acetylating agent such as acetic anhydride or an acetyl halide gives the corresponding compounds wherein the hydroxy group at 9-position is acetylated. For example, when clavulone-7 is treated with acetic anhydride in a usual manner, clavulone-8 is obtained. Besides, oxidation of the compounds obtained by the above reduction treatment with an appropriate oxidizing agent such as pyridinium chlorochromate gives the corresponding compounds wherein the hydroxy group at 9-position is converted into a keto group. For example, when clavulone-7 is treated with pyridinium chlorochromate, clavulone-11 is obtained. Moreover, when clavulone-1, clavulone-2 and clavulone-3 are reduced by a conventional catalytic reduction, for example, by hydrogenating in the presence of a catalyst such as palladium-carbon, there are obtained the corresponding compounds wherein the double bond is wholly or partially saturated, i.e. clavulone-12 and clavulone-13 from all of the clavulone-1 to clavulone-3.
The clavulone deivatives (I) of the present invention have excellent pharmacological activities such as anti-inflammatory and anti-tumor activities. The pharmacological activities of the clavulone derivatives are shown by the following experiments.